Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis

Lana C Pinto,Sabrina S Barkan,Jorge L Gross,Dimitris V Rados,Cristiane B Leitão

doi:10.1038/s41598-017-19055-6

Abstract

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting 24 weeks or more that compared DPP-4 inhibitors with placebo or other antihyperglycaemic agents. A total of 59,404 patients were included. There was no relationship between the use of DPP-4 inhibitors and pancreatic cancer (Peto odds ratio 0.65; 95% CI 0.35–1.21), and the optimal sample size was reached to determine a number needed to harm (NNH) of 1000 patients. DPP-4 inhibitors were associated with increased risk for acute pancreatitis (Peto odds ratio 1.72; 95% CI 1.18–2.53), with an NNH of 1066 patients, but the optimal sample size for this outcome was not reached. In conclusion, there is no association between DPP-4 inhibitors and pancreatic cancer, and a small risk for acute pancreatitis was observed with DPP-4 inhibitor use, although the latter finding is not definitive.

Highlights

Background treatment Metformin Naïve or OADsMetformin Diet, Exercise or OAD Metformin + Pioglitazone Insulin or Insulin + Metformin Metformin Metformin, Pioglitazone, Sulfonylurea or Insulin Metformin Metformin Metformin Naïve Metformin Diet, Exercise, Metformin or Sulfonylurea Thiazolidinedione OADs Naïve Non-incretin therapies OADs Naïve Metformin Metformin Metformin OADs or Insulin Diet + Exercise Naïve Metformin Naïve Insulin Naïve Metformin + Sulfonylurea Metformin Metformin Insulin Diet + Exercise OADs Metformin Diet + ExerciseBefore this review, three other meta-analyses evaluated the association between clinical use of dipeptidyl peptidase-4 (DPP-4) inhibitors and acute pancreatitis
The results of the present review indicate that the use of DPP-4 inhibitors is not associated with increased risk for pancreatic cancer
There seemed to be an association between the use of DPP-4 inhibitors and acute pancreatitis, the number of randomised patients was not sufficient for a firm conclusion and the estimated risk of acute pancreatitis is small

Summary

Introduction

Background treatment Metformin Naïve or OADsMetformin Diet, Exercise or OAD Metformin + Pioglitazone Insulin or Insulin + Metformin Metformin Metformin, Pioglitazone, Sulfonylurea or Insulin Metformin Metformin Metformin Naïve Metformin Diet, Exercise, Metformin or Sulfonylurea Thiazolidinedione OADs Naïve Non-incretin therapies OADs Naïve Metformin Metformin Metformin OADs or Insulin Diet + Exercise Naïve Metformin Naïve Insulin Naïve Metformin + Sulfonylurea Metformin Metformin Insulin Diet + Exercise OADs Metformin Diet + ExerciseBefore this review, three other meta-analyses evaluated the association between clinical use of DPP-4 inhibitors and acute pancreatitis. The other two[1,3] found an increased risk of acute pancreatitis in patients treated with DPP-4 inhibitors; they included only three large cardiovascular randomised trials, namely, EXAMINE, SAVOR-TIMI 53 and TECOS18–20. In these trials, a specialised committee adjudicated the diagnosis of acute pancreatitis. A specialised committee adjudicated the diagnosis of acute pancreatitis None of these reviews performed TSA to evaluate whether the results were definitive, and, more importantly, none of them evaluated the risk of pancreatic cancer associated with use of DPP-4 inhibitors

Objectives

Methods

Results

Conclusion